Abstract The proposed drug development will result in the design and development of a ligand-targeted liposome (LTL) that will aid in the targeted delivery of therapeutics to patients with Non-Small Cell Lung Cancer (NSCLC). We propose an innovative active targeting strategy and our technology exploits the stress response that occurs within the cancer cells following exposure to ionizing radiation. This liposome targets the neoantigen Glucose-Regulated Protein 78 (GRP78) which is overexpressed in NSCLC and is further induced when cancer cells are exposed to radiation, a standard of care for patients with NSCLSC. For patients with NSCLC, the 5-year overall survival rate is 15%. The difficulty in treatment is partly due to genetic tumor heterogeneity, patient heterogeneity, induced immunosuppression, and limited drug penetration. The impact of current cytotoxic chemotherapies on NSCLC is limited by lack of specificity hence the attendant cytotoxicity to normal cells, resistance to therapy and disease recurrence. We identified GRP78 through the use of bacteriophage displayed peptide libraries and subsequent affinity purification of surface proteins from cancer. The proposed research will advance our lead LTL?s towards IND enabling studies. We will design and optimize a new peptidomimetic based on modeling of our parent peptide to achieve stronger specificity and prolonged circulation. We will synthesize the peptidomimetics and generate the LTL and characterize the same. Furthermore, we will demonstrate cancer specificity and sensitivity of the LTL?s using in vitro and in vivo assays. At the end of the project term, we will have determined and validated the feasibility of our new LTL as an effective payload carrier and hence a therapeutic agent in NSCLC. In line with our long-term goal in the next phase of the project, we study the bio-distribution and drug loading capability and efficacy by conducting studies that will determine the therapeutic effects of peptide-conjugated cancer pharmaceuticals.